Effects of an FcγRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies

Genes Immun. 2019 Jul;20(6):462-472. doi: 10.1038/s41435-018-0038-8. Epub 2018 Jul 6.

Abstract

The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcγR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype. Our analysis revealed that the levels of four cytokines (IFNγ, IL-12, IL-2, TNFα) and global gene expression patterns differed between all three genotype classes. Surprisingly, the heterozygotes showed suboptimal T cell activation compared to cells from individuals homozygous for the higher-affinity FcγRIIA allele (GG; Arg/Arg). The results of this study demonstrate that IgG response varies among all rs1801274 genotype classes and results in profound differences in both cytokine responses and gene expression patterns in blood leukocytes. Because even heterozygotes showed dampened global responses, our data may provide insight into the heterogeneity of outcomes in cytokine release assays and immunotherapy efficacy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Antibodies / pharmacology*
  • CD28 Antigens / antagonists & inhibitors
  • CD28 Antigens / immunology*
  • CD3 Complex / antagonists & inhibitors
  • CD3 Complex / immunology*
  • Child
  • Genotype
  • Heterozygote
  • Homozygote
  • Humans
  • Interferon-gamma / blood
  • Interferon-gamma / metabolism
  • Interleukin-12 / blood
  • Interleukin-12 / metabolism
  • Interleukin-2 / blood
  • Interleukin-2 / metabolism
  • Leukocytes / immunology*
  • Leukocytes / metabolism
  • Middle Aged
  • Polymorphism, Genetic*
  • Receptors, IgG / genetics*
  • T-Lymphocytes / metabolism
  • Transcriptome / immunology
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Antibodies
  • CD28 Antigens
  • CD3 Complex
  • Fc gamma receptor IIA
  • Interleukin-2
  • Receptors, IgG
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma